Novel Ferrocene Derivatives Induce G0/G1 Cell Cycle Arrest and Apoptosis through the Mitochondrial Pathway in Human Hepatocellular Carcinoma.

Jianrong Zheng,Mingqing Tang,Ruian Xu,Chao Pi,Liao Zeng,Xiuling Cui,Hongjun Lin

doi:10.3390/ijms22063097

Abstract

In this study, detailed information on hepatocellular carcinoma (HCC) cells (HepG-2, SMMC-7721, and HuH-7) and normal human liver cell L02 treated by ferrocene derivatives (compounds 1, 2 and 3) is provided. The cell viability assay showed that compound 1 presented the most potent and selective anti-HCC activity. Further mechanism study indicated that the proliferation inhibition effect of compound 1 was associated with the cycle arrest at the G0/G1 phase and downregulation of cyclin D1/CDK4. Moreover, compound 1 could induce apoptosis in HCC cells by loss of mitochondrial membrane potential (ΔΨm), accumulation of reactive oxygen species (ROS), decrease in Bcl-2, increase in BAX and Bad, translocation of Cytochrome c, activation of Caspase-9, -3, and cleavage of PARP. These results indicated that compound 1 would be a promising candidate against HCC through G0/G1 cell cycle arrest-related proliferation inhibition and mitochondrial pathway-dependent apoptosis.

Highlights

Hepatocellular carcinoma (HCC) is the sixth most commonly diagnosed of malignant tumors worldwide [1], with approximately 841,000 new cases in 2018 [2]
A series of ferrocene derivatives were synthesized based on transition metal-catalyzed C−H functionalization [12]
The cell cycle of HCC cells was blocked at G0/G1 after being treated by compound 1 for 72 h (Figure 2)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the sixth most commonly diagnosed of malignant tumors worldwide [1], with approximately 841,000 new cases in 2018 [2]. A broad-spectrum kinase inhibitor, has been the first-line chemotherapeutic drug that can provide modest benefits for patients with advanced HCC; this drug does have limited effects and inevitably causes toxic reactions [4]. Toxic reactions caused by sorafenib have become increasingly prominent in clinical treatment, hand–foot syndrome [5]. It is urgent to develop a novel agent with low toxicity and high efficacy for the treatment of HCC. Ferrocene derivatives are becoming more and more popular in medicinal molecules due to their unique chemical structures, biological activities, low toxicity, and reversible redox behavior [6]. We have successfully developed novel protocols to build a series of ferrocene derivatives based on transition metal-catalyzed C-H functionalization [12], and have explored the bioactivities of ferrocenyl olefins [13]

Methods

Results

Conclusion